Hope on the horizon for Alzheimer's disease treatment?
Authors: None The Lancet Healthy Longevity
Journal: The Lancet Healthy Longevity (2022)

An estimate of one new diagnosis every 3 seconds, equating to 10 million new cases per year worldwide. More than 16 billion hours of unpaid carer work in 2021, in the USA alone. A global economic burden of US$2·8 trillion in annual costs expected by 2030; according to Alzheimer's Disease International, if it were a country, dementia would be the 14th largest economy in the world. It is easy to understand why heads turn when anything new happens in the field of Alzheimer's disease, the most common type of dementia. One such recent development was Eisai's and Biogen's joint announcement of results from Clarity AD, a phase 3 trial of lecanemab for the treatment of early-onset Alzheimer's disease. Lecanemab is a humanised monoclonal antibody that selectively binds to the soluble amyloid β protofibrils that are typical in Alzheimer's disease. Clarity AD compared lecanemab with placebo in patients aged 50–90 years with objective impairments in episodic memory, brain amyloid pathology, and various comorbidities (such as hypertension, diabetes, heart disease, obesity, and renal disease). Lecanemab met the primary endpoint of reduced clinical decline on the Clinical Dementia Rating–Sum of Boxes scale compared with placebo (27% reduction at 18 months; p=0·00005), which certainly offers some hope that the progression of early-onset Alzheimer's disease can at least be slowed and that patients’ cognition and memory could be preserved for longer. However, the field has been riddled with false hope in the past—as strikingly illustrated by the defunding of all three acetylcholinesterase inhibitors licensed for dementia in France due to an absence of apparent benefit in May, 2018, and, more recently, by the controversy around the US Food and Drug Administration (FDA)'s approval of aducanumab in June, 2021. As such, considering whether any new advance actually offers a benefit to patients is of utmost importance. Given that previous trials of anti-amyloid β antibodies, such as bapineuzumab, solanezumab, and gantenerumab, have not met their primary endpoints, perhaps what is truly novel here is not lecanemab showing an advantage over placebo in patients already diagnosed with Alzheimer's disease, but instead its follow-up study, the ongoing AHEAD 3-45 phase 3 trial (NCT04468659), in which lecanemab is being compared with placebo in people without any signs or symptoms of Alzheimer's disease, but who already have elevated brain amyloid accumulation. As argued by Sarah Gregory and colleagues in this issue, understanding and stopping (or at least slowing) the onset of Alzheimer's disease will only be possible if trial participants are recruited in the earliest stages of the disease, for a true proof of concept of a disease-modifying therapy. Although the results of AHEAD 3-45 are not expected before late 2027, it is encouraging to see the pharmaceutical industry and trial funders reacting to the Alzheimer's research community's clamour for change. Between 2003 and 2019, more than 200 investigational drugs for Alzheimer's disease either failed to meet clinical study endpoints or were abandoned; no single drug reached FDA approval for the treatment of the disease during this period, and the 25 years before this interval were almost as fruitless. Although it has been argued that the so-called amyloidocentric approach to drug development for the treatment of Alzheimer's disease is yet to yield any real patient benefit, perhaps the issue is not the drug, but that studies have repeatedly tried to test drugs with similar mechanisms of action in much the same way, not heeding warnings that late initiation of treatment, inappropriate dosing, and poor selection of trial participants were just as probable possible reasons for failure. WHO predicts that, by 2050, 139 million people globally will be living with dementia, of which Alzheimer's disease will contribute to approximately 60–70% of cases, and the majority of whom will be in low-income and middle-income countries. The associated economic and social burden in health-care costs, lost productivity from carers and patients, and even in the possible loss of human rights of people with Alzheimer's disease are far too great for Alzheimer's research to remain unchanged. The time is ripe for a change; or, in Gregory and colleague's words, for a “shift towards understanding Alzheimer's disease as (…) detectable and manageable decades earlier than the current symptomatic focus allows for”. Even if the slow gears of clinical research take years to start yielding real disease-modifying courses of therapy, any progress now, be it a few more weeks or months for patients to be with their families with better quality of life, will be of value for them and their families. Science disconnected: the translational gap between basic science, clinical trials, and patient care in Alzheimer's diseaseBoth research and clinical practice have traditionally centred on the dementia syndrome of Alzheimer's disease rather than its preclinical and prodromal stages. However, there is a strong scientific and ethical impetus to shift focus to earlier disease stages to improve brain health outcomes and help to keep affected individuals symptom-free (dementia-free) for as long as possible. We provide an overview of recent advancements in early detection, drug development, and trial methodology that should be utilised in the development of new therapies for use in brain health clinics. Full-Text PDF Open Access